Saturated and unsaturated 17-oxy-17-acyl-androstanones and derivatives thereof and process of making same



Patented Dec. 19, 1944 UNITED STATES PATENT OFFICE 2,3653% 7 sAmUnATEDANn'uNsA'runnrEn-rz-oxr-u- 'ACYL-ANDROSTANON 'TIVES ING SAME ES :THEREOF AND I' ERDCESS F ,MAK-

AND DERIVA- "Leopold "Ruzicka, Zurich, Switzerland, assignor, by mesneassignmentsi to .Ciba Pharmaceutical Products. Incorporated,

ration of New. Jersey Snmmit,:.N..J a corpo- No'Drawlng. Application November 10, 1939, Se-

rial'No. '303;90l. [In Switzerland November 19,

' ample, ALpregnene-li:l'l-diol-20-sone, A -pregpens-3:17-diol-20-one, pregnane- 3 17-diol- 2 0- one, A -pregnene-3-one-17:20edi0l, .n -pregnene- 321722041101, or homologues thereof such :as .A -21-methyl pregnene-3: 17-dio1-20-;one. The

,317-hydroxyl group may .be .intermediately protested .for example by an ester group. Such compounds partially ,esterified in-the 1'7; position,

scams; (or. 260-'397.4')

OI'; S62!Y8 as intermediates in :the manufacture of nroducts-oitherapeutic value.

Example 1 v 50.5 ,part of A -pregnene-3:l'lediol zo-one- 17- monoacetate (prepared, for exa le, from A '3acetoxy-pregnadiene .by treatment with osmiumtetroxide, acylation, partial saponific'ation, tritylation, alkaline ,saponificatio-n, oxidation, and acid hydrolysis) is dissolved in parts of acetoneandBO parts of benzene and, after ad dition of ,1 part .of aluminium tertiary butylate, boiled under reflux for several hours. Water and dilute hydrochloric'acid are then added, the

reaction product is extracted with ether, :the

ether solution washed until neutral, dried, and evaporated. .The residue contains the .l'l-oxyprogesterone acetate whichmay be separated :may be obtained forexample by partial saponi' fication of thecorresponding polyester. Ins-such circumstances :the ester groupstmayibe the same or different. It is especially advanta eousjto start from'compounds containing in 1711 5113101} an ester group which is relativelydifiioult to saponify. The partial saponificationis carried 'out in .a manner in itself known, for example. by hydrolysis or alcoholysis in weak alkalineor .weak acid solution. As oxidizing-agents there are used those known to the expe-rtassuitable for "conversion of an alcohol group into a keto :group (compare 'J; Houhen-Weyl, Die .Methoden der organischen' Chemie, 3d. edition,=vol, z,,p ge .47 if.) There come into question'chrcmic acid in glacial acetic acid, metals and metal oxides, ,suchas copper powder, cupric oxide and the like,

.There has also been proved advantageousjthe treatment-with carbonyl. compounds in thepres- .ence =of'catalysts, for,instance metal alcoholates ohmetalacylates. If desired a biochemioal jow idation may al'sobeused. Existing double inkagesqmayz'be; protected in known manner.

The process produces saturated or unsaturated 17 oxy 17 acyl androstanones or derivatives thereof, such as esters or enol esters. The esters obtained may be saponified in known manner by the help of hydrolyzing agents. The free 17-oxy compounds may be converted into any desired esterified derivatives, for instance into any esters or enol esters, in the latter'case the ester groups being the same or different.

The new compounds are of use in therapeutics ,chromatographicallyby use' of aluminium oxide and then purified .by recrystallization from methanol. For the purpose.of saponification, 1 part of this acetate dissolved in parts of methanol and-the solution is mixed with 5 parts ofa solution of 10 per cent strength of potassium hydroxide in methanol and boiled under reflux for .3 hours After working up, the 1'7-oxyprogesterone iis recrystallized from methanol. As oxidizing agent, for example, chromium trioxidemiglacial acetic acid may be used in place of acetonein the presence of aluminium tertiary butylate. In this case it is advantageous to provide for intermediate protection of the double linkage, .for instance :by 'bromination, with subsequentsplitting ofi of the-bromine, for example y meansof zinc dust.

:As .parent' material ther may also he used .A '-3 -'transacetoxy-17 -benzoxy--pregnene-zo-one. If the free A -pregnene-3:l7-diole20 one is used as the starting point, the .l'I-oxy-progesterms .is also obtained,

In .yyhollysim'ilttr manner there may ,becbtrained the JM-Zl-methyl-171oxy pregnenea3 2.0-. .dione.

.Ea'amp l e 2 3:3 parts of A -pr'egnene-17:2D-diol-3 one-17 acetate (prepared for example by reaction of 17- ethenyl-testosterone with perphthalic acid, hydrogenation of the oxide with a palladiumcalcium carbonate catalyst, energetic acetylation, and partial saponification, or, also, from the known A: -pregnene-17:20-diol-3-one by ener- I getic acetylation and partial saponificaticn) are dissolved in '60 parts of chromic acid-resistant glacial acetic acid, a solution of 1 part of chromium trioxide dissolved in 15 parts of acetic acid of 90 per cent strength is added with cooling and the whole is allowed to stand 24 hours at room temperature. It is then poured into 500 parts of water, the reaction product extracted with ether and this solution is washed with dilute soda solution and water, dried and evaporated in a vacuum. The l'I-oxy-progesterone acetate I described in Example 1 may be obtained from the residue, and this may also be converted into the free l'l-oxy-progesterone as is there described. By more or less energetic treatment with acylating agents, the latter may be converted into other types of esters, for example into the l'Z-acetate-S-enolacetate or into the 1'!- monopropionate.

Example 3" the 21-position by an unsubstituted alkyl radical, unsaturation with respect to the carbon atom 3 being in the unsaturated 3-hydroxy compounds in the e-position and in the unsaturated 3-keto compounds in the a-position.

3. Process for the manufacture of unsaturated l'i-hydroxy-17 -acyl-androstanones and their derivatives, comprising causing oxidizing agents to act on a member of the group consisting of unsaturated pregnanolones and pregnandiols, which contain in the 1'7 -position a free hydroxyl group, and the corresponding compounds substituted in the 21-position by an unsubstituted alkyl radical,

tained from the ether solution as described in v the previous example.

When starting from Zl-methyl-pregnane- 3:17:20-tri0l (prepared for example from A -l'7- allyl-androstene-3 l'7-diol by gentle acetylation. hydrogenation, dehydration, as well as treatment with osmium tetroxide and sodium sulphite), the 21-methyl-pregnane-li-oleli:ZO-dione is obtained in an analogous manner. By energetic treatment with acylating agents, this may be converted into its 17-mono-esters, for example the acetate or propionate.

Instead of ZI-methyl-pregnane-triol otherhomologous l'i-oxy-pregnanolones or pregnandiols may be used as starting material.

What I claim is:

1. Process for the manufacture of unsaturated 17-hydroxy-ll-acyl-androstanones and their derivatives, comprising causing oxidizingagents to act on a member of the group consisting of unsaturated pregnanolones and pregnandiols, which contain in the 17-position a member of the group consisting of a free and protected hydroxyl group, and the corresponding compounds substituted in the 21-position by an unsubstituted alkyl radical, unsaturation with respect to the carbon atom 3 being in the unsaturated 3-hydroxy compounds in the ,s-position and in the unsaturated 3-keto compounds in the a-position.

2. Process for the manufacture of unsaturated unsaturation with respect to the carbon atom 3 being in the unsaturated B-hydroxy compounds in the c-position and in the unsaturated 3-keto compoundsjn the oc-DOSitiOIl, with intermediate protection of the l'l-ahydroxyl group.

4. Process for the manufacture of unsaturated II-hydroxyl7-acyl-androstanones and their derivatives, comprising causing oxidizing agents to act on a member of the group consisting of unsaturated pregnanolones and pregnandiols, which contain in the l'l-position a free hydroxyl group, and the corresponding compounds substituted in the 2l-position by an unsubstituted alkyl radical, unsaturation with respect to the carbon atom 3 being in the unsaturated 3-hydroxy compounds in the p-position and in the unsaturated 3-keto compounds in the a-position, with intermediate protection of the double linkages present.

5. Process for the manufacture of unsaturated 17-hydroxy-l'7-acy1 androstanones and their iderivatives, comprising causing oxidizing agents to act on a member of the group consisting of unsaturated pregnanolones and pregnandiols, which contain in the 17-position a free hydroxyl' group, and the corresponding compounds substituted in the 21-position by an unsubstituted 'alkyl radical, unsaturation with respect to the carbon atom 3 being in the unsaturated 3-hydr'oxy compounds in the c-position and in the unsaturated 3-keto compounds in the oc-POSitiOIl, and treating the products thus obtained with acylating agents.

6. A A -21-methyl-pregnene-3:20-dione substituted in the l7-position by a member of the group consisting of a free and an acylated hydroxyl group.

7. A A -21-methyl-pregnene-3:ZO-dione substituted in the 17-position by a free hydroxyl l'l-hydroxy-l'Z-acyl-androstanones and their deso rivatives, comprising causing oxidizing agents to act on a member of the group consisting of unsaturated pregnanolones and pregnandiols, which contain in the 17-position a free hydroxyl group, and the corresponding compounds substituted in group.

8. The 3-keto-l'l-hydroxy-androstanes which are unsaturated in the position 1 and which contain in the IY-position the grouping COCH2R,' wherein R is a member or the group consisting of hydrogen and alkyl.

9. A member of the group consisting of the unsaturated ,S-keto-pregnane-20-cnes, which contain in the 17-position a member of the group consisting of a free and an acylated hydroxyl group, and the corresponding compounds substituted in the 2l-position by an unsubstituted alkyl- "radical, unsaturatio n with respect to'the carbon ator'nS being in theposition 1.

LEOPQLDRU'ZICKA. 

